This invention relates to compounds for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts.
Osteoclasts are multinucleated cells of up to 400 .mu.m in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
More specifically, osteoclasts are believed to exist in at least two physiological states. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone.
Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration. The most abundant integrin in osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or .alpha.v.beta.3, thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to .alpha.v.beta.3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that .alpha.v.beta.3 ligands can be used effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Additionally, .alpha.v.beta.3 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration and angiogenesis (formation of new blood vessels), and inhibiting viral disease. Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine, 12th ed., 1991). .alpha.v.beta.3 antagonists, which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor .alpha.v.beta.5. A monoclonal antibody for .alpha.v.beta.5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model; M. C. Friedlander, et.al., Science 270, 1500-1502, 1995. Thus, compounds that antagonize .alpha.v.beta.5 are useful for treating and preventing macular degeneration, diabetic retinopathy, and tumor growth.
In addition, certain compounds of this invention antagonize both the .alpha.v.beta.3 and .alpha.v.beta.5 receptors. These compounds, referred to as "dual .alpha.v.beta.3/.alpha.v.beta.5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
It is an object of the present invention to identify compounds which bind to the .alpha.v.beta.3 receptor, .alpha.v.beta.5 receptor or both the .alpha.v.beta.3 and .alpha.v.beta.5 receptors.
It is a further object of the invention to identify compounds which act as antagonists of the .alpha.v.beta.3 receptor. It is another object of the invention to identify .alpha.v.beta.3 antagonist compounds which are useful agents for inhibiting: bone resorption mediated by osteoclast cells, restenosis, atherosclerosis, inflammation, diabetic retinopathy, macular degeneration and angiogenesis in animals, preferably mammals, especially humans. Still another object of the invention is to identify .alpha.v.beta.3 antagonists which cause tumor regression and/or inhibit tumor growth in animals.
A further object of the invention is to identify .alpha.v.beta.3 antagonists useful for preventing or treating osteoporosis. An additional object of the invention is to identify .alpha.v.beta.3 antagonists useful for treating cancer.
It has now been found that the compounds of the present invention, .alpha.v.beta.3 ligands, are useful for inhibiting bone resorption in mammals. Thus, the compounds of the present invention are useful for preventing or reducing the incidence of osteoporosis. Additionally, the .alpha.v.beta.3 ligands of the present invention are also useful for treating and/or inhibiting restenosis, diabetic retinopathy, macular degeneration, viral disease, atherosclerosis and/or angiogenesis in mammals.